ertugliflozin/sitagliptin (Rx)

>10% (Ertugliflozin)

Female genital mycotic infections (9.1-12.2%)

1-10% (Ertugliflozin)

Volume depletion adverse effects (1.9-4.4%)

Male genital mycotic infections (3.7-4.2%)

Urinary tract infections (4-4.1%)

Headache (2.9-3.5%)

Vaginal pruritus (2.4-2.8%)

Increased urination (2.4-2.7%)

Nasopharyngitis (2-2.5%)

Back pain (1.7-2.5%)

Renal adverse effects (1.3-2.5%)

Weight decreased (1.2-2.4%)

Thirst (1.4-2.7%)

Frequency Not Defined (Sitagliptin)

Upper respiratory tract infection

Nasopharyngitis

Headache

Abdominal pain

Nausea

Diarrhea

Peripheral edema

Postmarketing Reports (Sitagliptin)

Hypersensitivity including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions

Hepatic enzyme elevations

Acute pancreatitis

Worsening renal function and acute renal failure

Bullous pemphigoid

Constipation

Vomiting

Headache

Myalgia

Pain in extremity

Back pain

Pruritus

Rhabdomyolysis

Contraindications

Hypersensitivity

Severe renal impairment, end-stage renal disease, or dialysis

Cautions

Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin reported; promptly discontinue if pancreatitis suspected

Necrotizing fasciitis of the perineum (Fournier gangrene) reported with SGLT2 inhibitors; signs and symptoms include tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, and have a fever above 100.4 F or a general feeling of being unwell; if suspected, discontinue SGLT2 inhibitor and start treatment immediately with broad-spectrum antibiotics and surgical debridement if necessary

Causes intravascular volume contraction; symptomatic hypotension may occur after initiating, particularly in patients with renal impairment, with low systolic blood pressure, on diuretics, or who are elderly

Ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, reported; before initiating, consider factors that may predispose patient to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse; monitor for ketoacidosis and temporarily discontinue in clinical situations known to predispose to ketoacidosis (eg, prolonged fasting owing to acute illness or surgery)

Renal impairment may occur owing to intravascular volume contraction; before initiating, consider factors that may predispose patients to acute kidney injury, including hypovolemia, chronic renal insufficiency, CHF, and concomitant medications (eg, diuretics, ACE inhibitors, ARBs, NSAIDs); consider temporarily discontinuing ertugliflozin in any setting of reduced oral intake or fluid loss; monitor for signs and symptoms of acute kidney injury, and, if evident, discontinue drug promptly and institute treatment

Serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization reported in patients receiving SGLT2 inhibitors

An increased risk for lower limb amputation (primarily of the toe) has been observed in clinical studies with another SGLT2 inhibitor; before initiating, consider factors that may predispose patient to increased risk of amputations (eg, history of prior amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers)

Heart failure has been observed in cardiovascular outcomes trials for 2 other DPP-4 inhibitors; consider the risks and benefits prior to initiating treatment in patients at risk for heart failure (eg, those with a prior history of heart failure, a history of renal impairment), and observe these patients for signs and symptoms of heart failure during therapy

Genital mycotic infections may occur; patients with history of genital mycotic infections and uncircumcised males are more susceptible

Serious hypersensitivity reported with sitagliptin, including anaphylaxis, angioedema, and exfoliative skin conditions, including Stevens-Johnson syndrome (see Contraindications)

Dose-related increases in LDL-C reported

Severe and disabling arthralgia reported in patients taking DDP-4 inhibitors; may occur at any time; symptoms relieved upon discontinuation

Bullous pemphigoid requiring hospitalization reported with DPP-4 inhibitors; patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor

No conclusive evidence of macrovascular risk reduction with empagliflozin or any other antidiabetic agent

Drug interaction overview

• Hypoglycemia risk increased with insulin and insulin secretagogues (eg, sulfonylureas); a lower dose of insulin or insulin secretagogue may be required
• Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors, as SGLT2 inhibitors increase urinary glucose excretion and lead to positive urine glucose tests; use alternative methods to monitor glycemic control
• Monitoring glycemic control with 1,5-AG assay is not recommended, as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors; use alternative methods to monitor glycemic control
• Coadministration with sitagliptin has shown a slight increase in digoxin AUC (11%) and mean peak drug concentration (18%); no dosage adjustment of digoxin require, but monitor appropriately

Pregnancy

Ertugliflozin

• Based on animal data showing adverse renal effects, not recommended during the second and third trimesters of pregnancy
• Data are limited in pregnant women and are not sufficient to determine a drug-associated risk of adverse developmental outcomes; there are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy

• Animal data

  • In animal studies, adverse renal changes were observed in rats when ertugliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy; doses ~13 times the maximum clinical dose caused renal pelvic and tubule dilatations and renal mineralization that were not fully reversible
  • There was no evidence of fetal harm in rats or rabbits at exposures of ertugliflozin ~300 times higher than the maximal clinical dose of 15 mg/day when administered during organogenesis

Sitagliptin

• There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to sitagliptin during pregnancy
• Health care providers are encouraged to report any prenatal exposure by calling the Pregnancy Registry at 1-800-986-8999

Lactation

Not recommended while breastfeeding

Unknown if distributed in human breast milk

Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney

Because of the potential for serious adverse reactions in a breastfed infant, advise women that ertugliflozin/sitagliptin is not recommended while breastfeeding

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Ertugliflozin: Selective sodium-glucose transporter-2 (SGLT2) inhibitor; lowers the renal glucose threshold (ie, the plasma glucose concentration which exceed the maximum glucose reabsorption capacity of the kidney); lowering the renal glucose threshold results in increased urinary glucose excretion

Sitagliptin: Dipeptyl peptidase-IV (DPP-4) inhibitor; increases and prolongs incretin hormone activity, which is inactivated by DPP-4 enzyme; incretins increase insulin release and synthesis from pancreatic beta cells and reduce glucagon secretion from pancreatic alpha cells

Absorption

Ertugliflozin

• Peak plasma time: 1 hr (fasting); 2 hr (high-fat, high-caloric meal)
• Peak plasma concentration, steady-state: 81.3 ng/mL (5 mg qDay); 268 ng/mL (15 mg qDay)
• AUC, steady-state: 398 ng⋅hr/mL (5 mg qDay); 1,193 ng⋅hr/mL (15 mg qDay)
• Steady-state is reached after 4-6 days
• Bioavailability, 15 mg dose: ~100%

Sitagliptin

• Peak plasma time: 1 hr
• Bioavailability: 87%

Distribution

Ertugliflozin

• Vd, steady-state: 85.5 L
• Protein binding: 93.6%
• Blood-to-plasma concentration ratio of ertugliflozin: 0.66

Sitagliptin

• Vd: 198 L
• Protein binding: 38%

Metabolism

Ertugliflozin

• Major metabolic pathway for ertugliflozin is UGT1A9 and UGT2B7-mediated O-glucuronidation to 2 glucuronides (pharmacologically inactive at clinically relevant concentrations)
• CYP-mediated (oxidative) metabolism of ertugliflozin is minimal (12%)

Sitagliptin

• Primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8

Ertugliflozin

• Half-life: 16.6 hr
• Clearance: 11.2 L/hr
• Excretion, oral [14C]-ertugliflozin solution: Feces (40.9%); urine (50.2%)
• Excretion, unchanged ertugliflozin: Feces (33.8%); urine (1.5%)

Sitagliptin

• Half-life: 12.4 hr
• Renal clearance: 350 mL/min
• Excretion: 87% urine; 13% feces

Oral administration

Take in the morning qDay, with or without food

Missed dose

• Take it as soon as you remember
• If it is almost time for scheduled next dose, skip missed dose and take the next regularly scheduled time
• Do not take 2 doses of ertugliflozin at the same time

Storage

Store at room temperature between 68-77°F (20-25°C)

Keep tablets dry

Store blister packs in the original package